Mantle cell lymphoma (MCL) is an aggressive lymphoid neoplasm considered incurable with current therapies. However, recent studies have recognized a subtype of leukemic non-nodal MCL (nnMCL) with indolent course that may be amendable to conservative management for long periods. The mechanisms leading to this disparate behavior are not well known. Furthermore, biological criteria to justify conservative management or determine the most appropriate treatment are not well defined. Previous studies have shown the relevance of CCND1 and SOX11 oncogenic events in MCL deregulating cell cycle, B-cell differentiation program and tumor/microenvironment interactions combined with alterations in the DNA damage response (DDR) and survival pathways. However, these events do not capture the full clinical heterogeneity. We hypothesize that this diversity may stem from the different cell-of-origin of the tumors combined with genomic instability that seems to run in parallel with increasing changes in their epigenetic profile. The long term goal of our project is to understand the genomic, epigenomic and molecular mechanisms driving the biological and clinical diversity of MCL, to define targets that may open new therapeutic strategies and to identify biomarkers that can provide strong biological support for management decisions. Our specific aims are: 1) To investigate the role of CCND1 in the generation of MCL diversity, beyond its cell cycle regulation, promoting chromosomal instability or dysregulating other cellular processes and possible interactions with SOX11. We will use different cell models overexpressing and silencing CCND1 in different cell contexts of SOX11 expression in order to study DNA replication stress, interactions of CCND1 with the replication and transcription machineries, activation of DDR, and strategies to interfere with these mechanisms; 2) To identify secondary genomic and epigenetic alterations that may drive the different clinical and biological behavior of conventional and non-nodal MCL. We will exploit the recent whole genome/epigenomic data generated by our group and will complete the landscape of alterations in metachronic paired samples at diagnosis and progression or relapse. We will also characterize the progressive epigenomic changes in relationship to the genomic complexity of MCL and define their role in the clinical evolution of the patients; and 3) To identify novel biomarkers for therapeutic intervention and risk stratification of the patients beyond the proliferation activity and validate their clinical impact in large cohorts of patients with both MCL subtypes. This integrated genomic/epigenomic perspective of MCL together with a better understanding of the mechanisms leading to its genomic instability should provide solid biological bases for new management strategies and targets for therapeutic intervention.